We propose to determine at which levels of the metastatic cascade malignant cells from non-metastatic primary cancers are inhibited from generating clinically overt metastases. Experiments will be made to assess the behavior of these murine tumors at each of the sequential steps of metastasis: (1) Local invasion of normal tissues, using organ culture techniques, (2) separation of cancer cells from the primary lesion using in vitro model systems, (3) dissemination to distant organs by direct sampling of tumor-draining vessels and the systemic ciculation, (4) extravasation using organ cultures, and (5) covert metastasis development as assessed by bioassay procedures. The behavior of cells from each non-metastatic tumor will be compared with that of each other, low and high metastatic murine tumors at each level. The points of divergent behavior will be identified and some of the reasons for differences in patterns of metastasis determined. These studies should provide a better understanding of the complex metastatic process as a whole and provide information relevant to which stages of metastasis offer greatest opportunities for more effective inhibition of metastases in patients with cancer.